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In a full context of the structure, function, and interactions of the components of the pyruvate dehydrogenase complex (PDC), our research seeks to elucidate the short-term regulation of the mammalian PDC. The primary target is understanding the structure, molecular interactions and effector control of the pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) isoforms. PDKs phosphorylate and inactivates the E1 (pyruvate dehydrogenase) component and PDPs dephosphorylate and reactivate E1. Differences in the operation and the effector responsiveness of the kinase and phosphatase isoforms are dependent upon differences in the functional interplay of the 4 PDK isoforms and 2 PDP isoforms with the dihydrolipoyl acetyltransferase (E2) component and E3-binding protein (E3BP). To alter kinase and phosphatase function and regulation, E2 serves as an anchoring scaffold, as an adaptor protein directly aiding efficient phosphorylation and dephosphorylation, as a processing unit in translating effector signals, and as a direct allosteric agent in consequentially altering regulatory enzyme activities. We have uncovered these roles, as well as an adaptor role of E3BP in the case of one PDK isoform, and seek to learn the molecular basis by which these occur. Our efforts are aided by advances that we have made in developing E. coli expression systems for making most components (E1, E2, E2-E3BP, E3, 4 PDKs, catalytic subunit of PDP1) and a large number of E2 constructs. We use a combination of standard enzymology, molecular biology, and biophysical techniques.